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T.

Kietzmann1
E. Y. Dimova1
D. Flügel1
Oxygen: Modulator of Physiological and
J.-G. Scharf2 Pathophysiological Processes in the Liver
Sauerstoff: Modulator von physiologischen und pathophysiologischen Prozessen

Übersicht
in der Leber

Zusammenfassung Abstract

Molekularer Sauerstoff hat bedeutende Funktionen als Substrat Oxygen has important functions as substrate for biochemical re-

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bei einer Reihe biochemischer Reaktionen und als Signalmolekül actions and as modulator of gene expression. In the liver, the
bei der Modulation der Genexpression. Dies ist besonders mar- physiologically occurring oxygen gradient is a major effector of
kant in der Leber, wo der physiologisch vorhandene Sauerstoff- metabolic zonation. In addition, cross-talks between the O2 sig-
gradient bedeutend für die metabolischen Zonierung ist. Neben naling and nutrient signaling chains initiate a dynamic zonation
der Sauerstoffsignalkette sind auch die Nährstoff (Glukose)-ab- pattern. Under pathological situations, hypoxia appears to be a
hängigen Signalwege für die Zonierung bedeutend und so kön- major determinant for liver diseases and cancer. Thereby tran-
nen Wechselwirkungen zwischen Sauerstoffsignalweg und Glu- scription factors of the HIF family are activated whereas USF pro-
kosesignalweg mit für die dynamische Zonierung in der Leber teins have the potential to counteract HIFs. In addition, feedback
verantwortlich sein. Unter pathologischen Bedingungen kann mechanisms between hypoxia, HIF and the IGF axes appear to ex-
eine Unterversorgung des Lebergewebes mit Sauerstoff (Hypo- ist. Thus, the knowledge of these mechanisms may help to initi-
xie) ein entscheidender Faktor für die Progression von Leber- ate new therapies in diseases with disturbed O2 availability.
erkrankungen und insbesondere Krebs sein. Dabei spielen die 67
Transkriptionsfaktoren der HIF-Familie eine bedeutende Rolle; Key words
deren Wirkung kann partiell durch USF-Proteine antagonisiert Metabolic zonation · IGF binding protein-1 · HIF · PHD
werden. Weiterhin scheinen positive Rückkopplungsmechanis-
men zwischen Hypoxie, HIF und der IGF-Achse zu existieren, die
die Wirkung von Hypoxie oder Wachstumsfaktoren verstärken
können. Somit kann die genaue Kenntnis der einzelnen Signal-
wege und ihrer Wechselwirkungen eventuell dazu beitragen
neue Therapiestrategien für Erkrankungen zu entwickeln, die
durch eine veränderte Sauerstoffverfügbarkeit gekennzeichnet
sind.

Schlüsselwörter
Metabolische Zonierung · IGF Bindungsprotein · Hypoxie · HIF ·
Tumor

affiliation
1
Department of Biochemistry, Faculty of Chemistry, University of Kaiserslautern
2
Medizinische Klinik und Poliklinik, Georg-August-Universität, Göttingen

correspondence
Dr. Thomas Kietzmann · Department of Biochemistry, Faculty of Chemistry, University of Kaiserslautern ·
67663 Kaiserslautern · Tel.: ++ 49/6 31/2 05 49 53 · Fax: ++ 49/6 31/2 05 3419 · E-mail: tkietzm@gwdg.de

bibliography
Z Gastroenterol 2006; 44: 67 – 76 © Georg Thieme Verlag KG Stuttgart · New York
DOI 10.1055/s-2005-858987
ISSN 0044-2771
Introduction In the original model of metabolic zonation, only these two zones
were distinguished because enzyme activities or contents were
With its appearance in the atmosphere, molecular oxygen (O2) be- high in the first half and low in the second half of the acinus or
came essential for the life of various organisms. All aerobic living vice versa. For example, the glucose-forming enzymes phospho-
organisms from bacteria to humans possess mechanisms to main- enol pyruvate carboxykinase (PCK1), fructose 1,6-bisphosphatase
tain O2 homeostasis that is essential for survival. Especially in and glucose 6-phosphatase had higher levels periportally whereas
mammals, the proper and integrated functions of the respiratory, glucokinase (GK) and liver type pyruvate kinase (L-PK) had higher
cardiovascular and hematopoietic systems contribute to the up- levels perivenously [4]. Apparently, the periportal cells have the
take of O2 from the environment and its distribution to every cell higher capacity for glucose release via gluconeogenesis, while the
of the body. Under physiological conditions, the average oxygen perivenous cells have the higher capacity for glucose utilization
tension in human arterial blood is between 74 to 104 mm Hg via glycolysis. This observation constituted the basis for the model
(104 – 146 µmol/L) and in venous blood between 34 to 46 mm Hg of metabolic zonation, which was then extended to include not
(48 – 64 µmol/L) [1, 2] and a failure within the O2 delivering sys- only carbohydrate but also other major pathways [7 – 11].
tems may contribute to the pathophysiology of common causes
Übersicht

of mortality in the developed world, including chronic lung dis- Within the acinus the blood flows from the terminal portal veins
ease, myocardial infarction, stroke, fibrosis and cancer. and arterioles of the portal triad into the central vein via the sinu-
soids and due to metabolism and elimination, respectively, con-
On the cellular level O2 is used as a substrate for a number of bio- centration gradients of substrates such as oxygen and hormones
chemical reactions. Especially in the mitochondrial respiratory are formed [4, 12, 13]. Especially, the gradient of oxygen appears
chain it serves as the final electron acceptor during the combus- to be of importance for the zonal expression of the genes encoding
tion of organic substrates such as glucose to yield energy in the carbohydrate-metabolizing enzymes [4, 12]; its partial pressure

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form of ATP. Although necessary for ATP generation, too much O2, (free concentration) is about 60 – 65 mm Hg (84 – 91 µmol/L) in
i. e., hyperoxia, results in the generation of reactive oxygen inter- the periportal blood and falls to about 30 – 35 mm Hg (42 –
mediates and potentially lethal damage to membranes, lipids and 49 µmol/L) in the perivenous blood [14, 15].
DNA whereas hypoxia can result in a failure to generate sufficient
ATP for maintenance of essential cellular functions [3]. The observation that O2 can significantly modify carbohydrate me-
tabolism has long been known from studies in perfused livers.
In addition to O2, organic substrates need to be present for the However, difficulties arise during these studies with the isolated
generation of ATP otherwise severe complications may arise. Par- perfused liver since the pO2 in the perfusate decreases consider-
ticularly, in mammals glucose serves as one of the major energy ably from the upstream to the downstream zone. Primary hepato-
substrates and thus not only O2 concentrations but also blood glu- cyte cultures have brought about an alternative tool due to the fact
cose levels must be tightly regulated within a narrow physiologi- that they can be kept under a defined pO2 resembling arterial peri-
68 cal range. portal (experimental gas atmosphere: 13 – 16 % O2 [v/v]) and peri-
venous (5 – 8 % O2 [v/v]) pO2.
Among other functions, the liver serves as the major glucostat of
the body, thus keeping blood glucose levels constant. This is By using these cells, it could be shown that net glucose uptake oc-
brought about by a functional specialization of the liver parenchy- curred above 2 % O2 and stayed constant above 4 % O2. Net glycogen
ma known as metabolic zonation. Thereby O2 appears to act not synthesis occurred only above 4 % O2 while CO2 formation in-
only as the essential electron acceptor of energy metabolism, but creased in direct proportion to the oxygen concentration up to 6 %
also as a major modulator of metabolic zonation under physiologi- O2 (v/v) and then it stayed essentially constant. In addition, the
cal conditions and as a determinant of liver diseases under patho- gluconeogenic-dependent net glucose output and net lactate up-
logical conditions [4, 5]. take increased clearly up to 6 % O2 and even higher pO2 values in-
itiated a further but more moderate increase. The net glucose out-
put initiated by glycogen breakdown increased below 2 % O2 and
Metabolic Zonation of the Liver, Oxygen Gradients and the net lactate output below 6 % O2 in perivenous-like cells. Most
Modulation of Carbohydrate Metabolism by O2 interestingly, the net flow between glucose 6-phosphate and pyr-
uvate in the gluconeogenic direction was enhanced with increas-
A special feature of liver metabolism consists in its metabolic zo- ing pO2 in the periportal-like cells and, conversely, it was en-
nation which means that different pathways are located in differ- hanced in the glycolytic direction with decreasing pO2 in the
ent areas, i. e., zones, of the liver acinus's. The acinus's represents perivenous-like cells. Thus, both the periportal and the perivenous
the smallest functional unit of the liver based on the blood supply cells operate at higher efficiencies at their physiological pO2[12,
[6]. The liver receives nutrient-rich blood from the digestive sys- 16 – 18].
tem by the portal vein, and O2-rich blood by the hepatic artery. To-
gether with the bile duct, which secretes bile salts into the intes- The zonal distribution of the key enzymes and metabolic fluxes
tines, terminal branches of the portal vein and hepatic artery form has its basis in a zonated gene expression. The early studies de-
the portal triad. The portal triads are arrayed in a hexagonal fash- scribed that PCK1 and GK were induced to higher activities at peri-
ion and connected via sinusoids with the hepatic venules better portal and perivenous oxygen tensions, respectively [15, 18]. Then
known as central veins. The region around the portal triad is called it was shown that PCK1 activities were induced by glucagon to
the periportal zone, and the area around the central vein was higher levels under periportal pO2 and it was suggested that these
named the perivenous, pericentral or centrilobular zone. effects are regulated at the transcriptional level [15]. Indeed, later

Kietzmann T et al. Oxygen: Modulator of … Z Gastroenterol 2006; 44: 67 – 76


studies fully supported this view and demonstrated that glucagon subunits (HIF-2α and HIF-3α) as well as two other ARNT isoforms
activated the transcription of the PCK1 gene maximally under (ARNT2 and ARNT3) are known (reviewed in [34]). Interestingly,
periportal pO2 [19, 20] and, reciprocally, insulin activated the tran- the HIF-1α subunit carries the sensitivity towards O2 and ARNT is
scription of the glucokinase gene maximally under perivenous pO2 not regulated by O2. In rat liver all HIF-α-subunits were found with
[20 – 23]. higher levels in the less aerobic perivenous zone, however, HIF-1α
and HIF-2α seem to be expressed in nearly if not all organs [35].
HIF-1α and HIF-2α appear to differ in their target gene specificity
O2 Responsive Elements and Transcription Factors [36, 37] whereas HIF-3α appears to differ in mediating the hypoxic
Controlling Gene Expression response or might also be a negative regulator [38, 39]. Likewise,
splice variants of HIF-3α, such as the mouse inhibitory PAS protein
Normoxia regulated expression (IPAS) and the human HIF-3α4 have been ascribed to have an inhi-
The transcriptional regulation of gene expression is usually bitory function on HIF-1α [40 – 42].
brought about by regulatory transcription factors which can be
grouped in different families and classes. In general, these proteins Most interestingly, hypoxia regulates HIF-1α predominantly on

Übersicht
are binding to specific regulatory DNA elements within a promo- the level of protein stability although evidence exists that it can
ter or enhancer of a gene. The DNA binding of the transcription also be regulated at the translational level [30, 38, 43 – 46]. The hy-
factors, in turn, can be affected by various reactions like phosphor- poxia-dependent regulation of the protein stability is brought
ylation, oxidation or oxygenation which can occur either directly about by the HIF-1α carboxy-terminal half which contains an oxy-
at the DNA binding domain or within other parts of the protein, gen-dependent degradation domain (ODD) [47] and two transacti-
usually called regulatory or transactivation domain. Thus, to un- vation domains (TADs) referred to as amino-terminal (TADN) and
derstand the O2-modulated transcriptional regulation of the PCK1 carboxy-terminal (TADC) TAD which are connected by an inhibi-

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gene in more detail and to identify the DNA element in the PCK1 tory domain [48, 49]. Normoxia destabilizes HIF-α subunits by
promoter where a putative O2-responsive transcription factor can O2-dependent hydroxylation of at least two proline residues
bind, rat hepatocytes were transfected with various PCK1 promo- (P402, P564) within the ODD [50, 51]. This is the prerequisite for
ter constructs. These experiments revealed that the O2 modulatory the binding of the von Hippel-Lindau tumor suppressor protein
effect on glucagon-dependent PCK1 expression was mediated via a (pVHL) [52 – 55]. In association with a multiprotein complex con-
normoxia response element (NRE) in the PCK1 promoter [24]. The taining elongins B/C, Cul2, and Rbx1, VHL forms a E3 ubiquitin li-
factor binding to the NRE is not known yet, however, the NRE DNA gase complex which then initiates ubiquitylation and proteasomal
binding activity was strictly dependent on the pO2 and susceptible degradation [53, 56 – 60]. The hydroxylation reactions are carried
to redox modifications [25]. The genes for other periportally ex- out by at least four HIF-α prolylhydroxylase domain containing
pressed and O2 modulated enzymes such as tyrosine aminotrans- proteins (PHD) [61 – 63] although the experimental support for
ferase and serine dehydratase have promoter elements identical to the latter one is limited [64]. Another hydroxylase named factor
the NRE of the PCK1 gene. Currently experiments are being carried inhibiting HIF (FIH) [65 – 67] prevents the recruitment of the coac- 69
out to establish whether these sequences can function as NREs. tivator CREB binding protein (CBP)/p300 by hydroxylating an as-
The results of these studies will then enable further screens to paraginyl residue (N803) in the TADC [68]. In addition, TADC can
identify the NRE binding factor. be modified by redox factor-1 (Ref-1) [69] and interact with ster-
oid receptor coactivator-1 (SRC-1) and transcription intermediary
Hypoxia regulated expression factor 2 (TIE-2) [70, 71].
The transcription factor hypoxia-inducible factor 1 (HIF-1) was
found to be involved in the hypoxia-induced expression of nearly, Interestingly, HIF-1α is not only responsive to hypoxia. A number
if not, all glycolytic enzymes. HIF-1 was initially identified as the of studies indicated that HIF-1α is responsive to hormones such as
transcription factor permitting the induction of the erythropoietin insulin [72 – 74], growth factors such as PDGF, EGF, FGF, TGF-ß and
(EPO) gene by hypoxia and is now considered to be the major reg- IGF-1 [75 – 77], coagulation factors such as thrombin [75], vasoac-
ulator of about 100 physiologically important genes among them tive peptides such as angiotensin II [76], cytokines [78], or carba-
the angiogenesis mediator vascular endothelial growth factor chol which activates muscarinic acetylcholine receptors [79] al-
(VEGF) or plasminogen activator inhibitor-1 (PAI-1) [26]. HIF-1 ready under normoxia. Moreover, HIF-1 has also been shown to
was found to be conserved from Caenorhabditis elegans via Droso- be activated by metal ions such as cobalt, calcium [80 – 83], chro-
phila melanogaster to Homo sapiens [27 – 30] suggesting that the mium and arsenite [84, 85] as well as by mechanical stress [86].
HIF-1 system played an essential role during evolution. HIF-1 is a The molecular basis by which these non-hypoxic stimuli induce
heterodimer composed of an HIF-1α and an HIF-1β-(ARNT) [31] HIF-1α is not completely known but may involve reactive oxygen
subunit and binds to hypoxia response elements (HRE) with the species generated either at the endoplasmic reticulum or within
consensus sequence 5′-BACGTSSK-3′ (B = G/T/C, S = C/G, K = G/T) mitochondria and various kinases [3] (Fig. 1).
[32] with the core sequence 5′-RCGTG-3′ (R = purine, A, G) [33]
which partially constitutes an E-Box sequence 5′-CANNTG-3′ Together, the O2 responsive transcription factors such as the so far
(N = any nucleotide). unknown NRE-binding factor or HIFs may contribute to the zonal
gene expression pattern within the liver acinus.
HIF-1α and ARNT belong to the basic helix-loop-helix and Per-
ARNT-Sim (PAS) domain proteins. In addition, two other HIF-α-

Kietzmann T et al. Oxygen: Modulator of … Z Gastroenterol 2006; 44: 67 – 76


Fig. 1 Integration of the O2 signaling casca-
de for modulation of gene expression in
hepatocytes. Under hypoxia, inhibition of
prolyl and asparaginyl hydroxylases (PHD
and FIH) stabilizes the HIF-1α subunit. The
activity of the hydroxylases and the stability
of HIF-1α can also be modified by reactive
oxygen species (ROS) which can be genera-
ted in different cellular compartments as a
response to different stimuli such as high
glucose. In the nucleus, HIF-1α dimerizes
with HIF-1β (ARNT) to form the HIF-1 dimer
which then binds to hypoxia responsive ele-
ment(s) (HREs) within the promoters of tar-
get genes, e. g., plasminogen activator inhi-
bitor-1 (PAI-1), IGF-1 and IGFBP-1. PAI-1 in
turn inhibits urokinase-type (uPA) and tissue-
Übersicht

type plasminogen activator (tPA)-mediated


generation of plasmin. In addition, via bin-
ding to vitronectin and integrins PAI-1 can
modify cell attachment. Like insulin, the
complex of IGF-1 and IGFBP-1 can initiate a
feedback cycle by activating ERK and/or PKB
pathways which contribute to increased
HIF-1α levels. Uptake of glucose into hepato-

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cytes is facilitated by GLUT2 and either glu-
cose or a metabolite can activate binding of
upstream stimulatory factors (USFs) or car-
bohydrate response element binding protein
(ChREBP) to the glucose-responsive element
(GlcRE) within glucose-responsive genes
such as pyruvate kinase (PKL). This GlcRE can
also function as a low affinity HRE (laHRE);
therefore, there might be a competition
among the transcription factors for occupy-
ing these elements.

70 Cross-Talk between O2-Dependent and Glucose-Dependent the glucose-responsive transcription factors and HIF-1 may act
Gene Expression through the same element.

According to the model of metabolic zonation for carbohydrate Indeed, physiologically occurring mild hypoxic conditions, i. e.,
metabolism, glucose release from glycogenolysis and gluconeo- perivenous pO2, activated L-PK expression. However, high glucose
genesis with the key regulatory enzyme PCK1 takes place prefer- enhanced L-PK gene expression only under periportal pO2; no in-
entially in the more oxygenated periportal zone; conversely, glu- duction by glucose was observed under perivenous pO2. Further
cose uptake for glycogen synthesis and glycolysis with the key analyses showed that the L4-GlcRE within the L-PK gene promoter
enzymes GK and L-PK occurs mainly in the less aerobic perivenous was sufficient to confer the modulation by O2 of the glucose-de-
zone. Interestingly, microdissection studies indicated higher L-PK pendent induction of the L-PK gene expression [101]. Reciprocally,
enzyme activity in the less aerobic perivenous zone [87, 88], a gene construct containing hypoxia response elements could be
where glucose uptake takes place. Moreover, it is known that glu- induced by glucose; however, the modulation by O2 was abol-
cose acts as a very potent activator of the L-PK gene expression. ished. Electrophoretic mobility shift assays then indicated that
Thus, it might be possible that both oxygen and glucose contribute the GlcRE resembles a low affinity HIF-1 binding site as well as a
to the zonated L-PK expression in a synergistic or non-synergistic binding site for USF-1 and USF-2. Thus, it might be that, in the pre-
manner. sence of glucose and low oxygen, an HIF-1 complex binds to the
GlcRE within the L-PK promoter and out-competes the glucose-re-
This view was supported by the findings that the glucose signaling sponsive USF complex which will then result in a reduction of the
chain for transcriptional activation of the L-PK gene ends up with glucose-dependent L-PK expression [101] (Fig. 1). Since HIF-1α is
the glucose-responsive transcription factors (USF, upstream sti- unstable under periportal pO2 this would also explain why glucose
mulatory factors [89 – 91] or the newly identified ChREBP [92]) induces L-PK expression predominantly only under periportal pO2.
binding to the L4 (– 168/– 145) element in the L-PK promoter. The action of the two factors HIF-1 and USF at the same element
This element consists of two imperfect palindromic E-boxes [93 – may then help to understand the dynamics of zonal L-PK expres-
95] and similar glucose-responsive elements (GlcRE) were found sion in the liver. Thus, in the fasted state, as in between meals, the
also within the Spot14 gene [96 – 98], the glucagon receptor gene, glucose-dependent induction of the L-PK gene expression is not
the hexokinase II gene [99] and the fatty acid synthetase gene present so that L-PK gene activation by venous pO2 predominates
[100]. In addition, the HIF-1 binding consensus sequence resem- and leads to the perivenous zonation of the enzyme as was shown
bles a partial E-box sequence and therefore it seems likely that in fasted rats [101]. In the fed state, the predominant L-PK gene ac-

Kietzmann T et al. Oxygen: Modulator of … Z Gastroenterol 2006; 44: 67 – 76


tivation by glucose would occur only in the periportal region as PAI activity are PAI-1, PAI-2, the protein C inhibitor and the pro-
observed in the livers of fed rats and this results in a diminution tease nexin-1. From these inhibitors, PAI-1 has the major physiolo-
of the zonation pattern and an about equal distribution of L-PK gical role and can be secreted from platelets, vascular endothelial
throughout the acinus [101, 102]. cells, vascular smooth muscle cells (VSMC) and several non-vascu-
lar cell types, among them hepatocytes (reviewed by [116]).
Further, a similar mode of competitive action between hypoxia
and glucose signaling was proposed from experiments with AS- Interestingly it was found that PAI-1 expression was markedly
30D hepatoma cells and the hexokinase type II promoter [99]. In- enhanced in the livers of rats with carbon tetrachloride (CCl4)-in-
terestingly, the interference of glucose and hypoxia signaling ap- duced perivenous cirrhosis [117]. This could be due to the cirrho-
pears not to be specific for liver and liver-derived cells since it sis-associated hemostasis and coagulopathy resulting in a more
was also shown that high glucose reduced hypoxia-dependent centrilobular hypoxemia [118]. Further, in the same model it was
HIF-1α protein stabilization and transactivity in dermal fibro- shown that fibrin deposits were present in the cirrhotic perive-
blasts and dermal microvascular endothelial cells [103]. Moreover, nous area [119].
the interaction of the signals glucose and oxygen (hypoxia) was

Übersicht
shown in experiments with HIF-1α deficient embryonic stem cells In addition to the findings in the liver, increased PAI-1 levels have
[104 – 106]. been found in a number of pathological settings associated with
hypoxia such as atherosclerosis, coronary heart disease, deep
Together, the cross-talk between the signals oxygen and glucose vein thrombosis, acute and chronic inflammatory lung disorders,
might represent a more common mechanism which might be im- chronic renal diseases, sepsis, hemorrhage and cancer metastasis
portant not only for gene regulation in metabolism but also for tu- (reviewed by [120]).
morigenesis or embryonic development.

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Indeed, experiments in primary cultured rat hepatocytes revealed
the molecular basis for the perivenous hypoxia-mediated en-
Oxygen as Modulator of Liver Disease hancement of PAI-1 expression. A PAI-1 promoter region contain-
ing two putative HREs was involved in the transcriptional up-re-
It is well known that hypoxia is a key factor for cell damage and gulation of PAI-1 expression by perivenous pO2. Mutation of
therefore perivenous hypoxia in particular may play a role in acute either HRE-1 or HRE-2 within the rat PAI-1 promoter abolished
and chronic liver injury. the induction by hypoxia. The transcription factor mainly respon-
sible for the hypoxia-dependent PAI-1 regulation was found to be
Several diseases in which the delivery of oxygen to the liver is re- HIF-1 acting mainly via HRE-2 as shown by cotransfections and gel
duced lead to perivenous hypoxia and can be associated with peri- shift assays [26]. In line with this, another study investigating the
venous damage: Heart failure (ischemic hepatitis) [106], obstruc- human PAI-1 promoter also found that HIF-1 enhanced PAI-1 ex-
tive lung diseases [107], gut ischemia [108, 109] or cases of indirect pression by binding to HRE-2 [121]. Although both HRE-1 and 71
drug hepatotoxicity (impairment of the celiac ganglion by the HRE-2 were involved in the PAI-1 induction by hypoxia, a differ-
acetylcholinesterase inhibitor tacrine) [110]. Further, direct hepa- ence appeared to exist between the two sites with respect to the
totoxicity is not only caused by hepatitis viruses but also by many affinity for HIF-1. Indeed, it was found by supershift and competi-
drugs like acetaminophen, chemicals like carbon tetrachloride and tion assays that upstream stimulatory factor-2 a (USF-2) bound
last but not least the “cultural poison” ethanol. The toxic metabo- with higher affinity to HRE-1 than to HRE-2 while HIF-1 bound
lites from these xenobiotics are formed in the liver and cause peri- with reversed affinity [122]. Remarkably, overexpression of USF-2
venous damage associated with perivenous hypoxia [110 – 112]. inhibited PAI-1 expression under normoxia and hypoxia. Mutation
of the HRE-1 in the PAI-1 promoter Luc constructs decreased USF-
After acute injury, the liver can be regenerated to restore the whole dependent inhibition of Luc activity whereas mutation of HRE-2
organ function whereas chronic injury often results in liver fibrosis was less effective indicating again that HRE-1 is the major USF
and cirrhosis associated with complications of advanced liver dis- binding site [122].
ease such as tumorigenesis. These processes are associated with
deposition and remodeling of cellular and extracellular compo- Based on these results it was proposed that a competition me-
nents in which the plasminogen/plasmin proteolytic system has chanism between USFs and HIF-1 is involved in the fine tuning of
been implicated. The urokinase-type (uPA) and tissue-type (tPA) PAI-1 gene expression. Thus, under normoxia, when HIF-1α is un-
plasminogen activators convert plasminogen to the active protease stable, the PAI-1 HREs are occupied by the constitutive present
plasmin. Although mainly known due to its role in fibrinolysis, transcription factor USF. Due to its inhibitory role, this binding
plasmin can also act on a number of molecules such as laminin, leads to a low level of PAI-1 expression. Under hypoxic conditions
collagen type IV, hepatocyte growth factor or transforming growth HIF-1α is stabilized and once in the nucleus it forms with ARNT
factor which play an important role in extracellular matrix turn- the active HIF-1 dimer. Active HIF-1 in turn, out-competes USFs
over, proliferation and tissue remodeling (reviewed by [113]). The from the HREs resulting in the induction of PAI-1 transcription
uPA and tPA mediated conversion of plasminogen into plasmin is (Fig. 1). The competition process will start at the low affinity USF
directly controlled by plasminogen activator inhibitors (PAIs) [114]. but high affinity HIF-1 binding site HRE-2 and later upon pro-
longed or more severe hypoxia, HIF-1 will also bind to the high af-
Plasminogen activator inhibitors (PAIs) belong to the serine pro- finity USF site HRE-1 [122].
tease inhibitor (serpin) family [115]. Among the molecules with

Kietzmann T et al. Oxygen: Modulator of … Z Gastroenterol 2006; 44: 67 – 76


Since a number of clinical studies demonstrated that high PAI-1 oxygen species, the HIF-prolylhydroxylases (PHDs) and the HIFs
levels in tumors indicate a poor prognosis [123 – 125] the balance themselves have been involved (Fig. 1). Interestingly, although
between HIF-1 and USF-2 may affect progression and metastasis. also considered as a negative regulator, transient transfection ex-
periments demonstrated an involvement of HIF-3α in the induc-
The importance of intratumoral hypoxia for progression is also in- tion of IGFBP-1. The role of HIF-2α and HIF-1α was less prominent.
dicated by the fact that a number of different tumors show ele- Further, overexpression of the HIF-PHDs lead to destabilization of
vated HIF-1α levels [126 – 128]. Further, the involvement of HIF HIFs, thereby attenuating the modulation by O2 of IGFBP-1 and - 4
was underlined by the fact that tumors derived from embryonic expression [138].
stem (ES) cells with inactivated HIF-1α genes (HIF-1α –/–) did
not express the angiogenic growth factor VEGF in response to Moreover, the expression of IGF-2, IGFBP-2, and IGFBP-3 was also
hypoxia resulting in poor blood vessel supply [104, 105]. Further, shown to be induced by hypoxia in bovine pulmonary artery en-
in athymic mice tumors derived from injected HepaC4 cells with dothelial cells [139], human hepatoma cells [140, 141], and neona-
a defective ARNT (HIF-1ß) and thus with a lack of the HIF-1 (HIF- tal rat retina [142], respectively. In line with this, another study
1α/HIF-1ß) heterodimer showed reduced vascularity and growth showed that IGF-2 and IGFBP-2 mRNA expression was dramati-
Übersicht

than tumors derived from the wild type Hepa-1 cells [128, 129]. cally reduced in HIF-1-deficient mouse embryonic fibroblastst
By contrast, USFs have been shown to have antiproliferative (MEFs), although hypoxia neither induced IGF-2 nor IGFBP-
properties; when overexpressed in rat embryonic fibroblasts they 2 mRNA expression in wild-type MEFs [143]. In the same study
inhibited E1A and c-Myc-induced cellular transformation and a IGFBP-4 mRNA expression was not affected by hypoxia or HIF-1
strong suppression of HeLa cell colony formation [130]. This impli- deficiency in agreement with a previous study [139, 143] suggest-
cates that USFs or small molecules acting as USF activators may be ing that HIF-1 regulates a subset of IGFBP family members in a
a treatment option in tumors. cell-type-specific manner.

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Among VEGF and PAI-1, a number of other factors, e. g., insulin- On the other hand, insulin, IGF-1 [144] and IGF-2 [143] have been
like growth factors (IGF-1 and IGF-2) and their respective binding shown to mediate an enhancement of HIF-1α protein levels.
proteins (IGFBPs) have been implicated as important mediators of Thereby, in HepG2 cells PI3K and ERK but not PKB appeared to be
growth, development and differentiation. The insulin-like and responsible for the enhancement of HIF-1α by IGF-1 [144]
cell-proliferative effects of the IGFs are mediated by the IGF-I re- whereas in colon cancer cells IGF-1 has been shown to act via the
ceptor and the insulin receptor [131], whereas the IGF-II/mannose MAPK and PI3K/PKB pathway [77]. Together, these findings sug-
6-phosphate receptor is involved in transport of lysosomal en- gest that in different tumor cells IGF-1 appears to regulate HIF-1α
zymes as well as in binding and internalization of IGF-2. IGF-1 induction via slightly different signaling pathways where the PI3K
can exert insulin-like effects on protein and carbohydrate metabo- and ERK1/2 are critically involved. In addition, these findings with
lism and growth factor-like effects on cell proliferation and survi- hepatoma cells and colon cancer cells point to clear differences
72 val [132]. Unlike insulin, IGFs are present in most biological fluids between certain types of tumors and the knowledge of these var-
as complexes with IGFBPs which modulate the availability of IGFs iations may then help to improve and to specify tumor therapies.
to exert their biological effects via interaction with specific cell
surface receptors [133 – 135]. So far, six high affinity IGFBPs have Thus, it appears that a positive reciprocal relationship between the
been identified differing in molecular mass, IGF binding proper- HIF-1 and insulin/IGF systems exits since IGF-1 and IGF-2 induce
ties, posttranslational modifications as well as tissue and develop- HIF-1 (Fig. 1) which, in turn, regulates the expression of genes en-
mental regulated expression. The IGFBPs appear to act as carrier coding IGF-2, IGFBP-1, IGFBP-2, IGFBP-3 and more indirectly
proteins in the circulation, as inhibitors of IGF action by preventing IGFBP-4. This regulation may be important for tumor develop-
access to IGF receptors, as IGF stabilizers and thus as amplifiers for ment and progression. When a tumor reaches a size of about
a mitogenic response by providing a stable source of available 3 mm3 further growth is associated with intratumoral hypoxia
growth factor [133]. which triggers induction of HIF-1 and expression of HIF target
genes necessary for vasculogenesis such as VEGF, cell adhesion
The liver has been recognized as a major source of circulating IGF- such as PAI-1 and for cell growth such as IGFs and IGFBPs. IGFs in
1 and of some IGFBPs [135]. The production of these proteins is turn can again lead to the induction of HIF-1 and thus potentiate
distributed between different hepatic cell populations. Rat hepa- expression of HIF-1 target genes even without hypoxia thus lead-
tocytes have been shown to secrete IGFBP-1, - 2 and - 4 whereas ing to more unrestricted growth and metastasis. This feedback cir-
IGFBP-3 is expressed primarily by non-parenchymal liver cells cle may be one of the underlying molecular mechanisms responsi-
[136]. In situ hybridization studies revealed that IGFBP-1 mRNA ble for increased IGF-2 levels associated with the occurrence of
expression is highest in the less aerobic perivenous region of the hepatocellular carcinomas (HCC) and especially with the invasive-
hepatic acinus and that transcript levels are reduced in the more ness of metastatic HCC cells [145, 146]. In addition, this regulatory
aerobic periportal area [137]. phenomenon has to be considered when patients with HCC are
treated with transarterial chemoembolization (TACE) for tumor
The direct influence of O2 on IGFBP expression was then demon- ablation. TACE results in a hypoxic insult of the tumor and the sur-
strated in rat primary hepatocytes. This study showed that the ex- rounding normal liver tissue which can trigger the HIF/IGF/IGFBP
pression of IGFBP-4 mRNA and protein are reduced under perive- circuit including increased IGF-2 levels. These increased IGF-2 le-
nous pO2 [138]. By contrast, perivenous pO2 enhanced IGFBP- vels might favor the occurrence of intra- and extrahepatic metas-
1 mRNA and protein expression. Within this cascade iron, reactive tases [147] that are frequently observed in these patients.

Kietzmann T et al. Oxygen: Modulator of … Z Gastroenterol 2006; 44: 67 – 76


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Übersicht
gen metabolism, glycolysis and gluconeogenesis by physiological
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